This was a large-scale cross-sectional population-based study enrolled 43345 individuals. In our study, the SIRI was associated with deteriorating cardiometabolic related biomarkers. A higher level of SIRI was independently related to increased incidence of cardiometabolic diseases and cardiometabolic multimorbidity. This association remained robust after adjustment of potential confounders. Our results filled the gap in the research of inflammation and CMM at population levels, suggesting that low grade chronic inflammatory status may have an inverse effect on different CMM status.
Although there is no evidence of the association between SIRI and CMM. A series of studies have shown SIRI was related to components of CMD(10, 21, 26). A cross-sectional study conducted in rural China reported that the highest tertile of SIRI was related with increased risk of metabolic disorder (OR = 2.092; 95% CI, 1.622–2.699) and cardiovascular disease (OR = 3.397; 95% CI, 1.958–5.849)(10). According to Kailuan cohort comprising 85154 individuals, SIRI was related to higher occurrence of stroke and myocardial infarction(26). Similarly, a study in Poland enrolled 699 patients with coronary artery disease reported that SIRI was associated with the severity of CAD(21). In line with these studies, we demonstrated that the increased SIRI was positively associated with the prevalence of DM (OR = 1.14; 95% CI, 1.09–1.19), coronary artery disease (OR = 1.13; 95% CI, 1.07–1.19), and stroke (OR = 1.11; 95% CI, 1.04–1.19). Our study together with previous evidence supported a positive dose-response relationship between SIRI and incidence of CMDs.
In fact, the presence CMD multimorbidity status can have a different effect on the long-term outcome(3, 4). In the Clinical Practice Research Datalink (CPRD) of 2,007,731 UK population, participants who had all three CMDs had a significantly higher all-cause mortality risk than those who had only one or two CMDs(4). Therefore, finding a diagnostic tool is also of great importance in clinical practice regardless of the fact that CMM only account for approximately 5% of the entire population. Consequently, this study evaluated the associations of SIRI with different CMD multimorbidity status, including single CMD component (DM/coronary artery disease/stroke), CMD (with more than one CMD), and CMM (with more than two CMDs). It is found that SIRI had positive correlations with all CMD multimorbidity groups.
SIRI is a comprehensive blood index employing three critical components on inflammation and immune response (neutrophils, monocytes, and lymphocytes). Due to this, it can be more robust in predicting the prevalence of diseases with complicated mechanisms like CMDs. Numerous studies have reported that SIRI showed a better predictive ability in patients with esophageal squamous cell carcinoma(27), stroke(16), and acute coronary syndrome(9, 20) compared to NLR, MLR and PLR. The results of our study also indicated that SIRI has a better diagnostic value for CMD and CMM than those traditional inflammatory biomarkers. Additionally, Wang and his colleague also found SIRI rather than NLR showed a significant association with the risk of metabolic diseases, suggesting that simple inflammatory biomarker fails to diagnose the CMDs in some situations(10).
The mechanism underlying the association between SIRI and cardiometabolic multimorbidity has not been fully understood, but it may be linked to chronic inflammation and abnormal activation of the immune system. Neutrophils are the most abundant leucocytes with a short life span which has been traditionally viewed as a biomarker of cardiovascular inflammation(28). High neutrophil counts promote vascular inflammation and are a predictor of future cardiovascular events(29). In addition, NETosis, a cell death subtype which refers to the process of releasing neutrophil extracellular traps (NETs) by neutrophils, is also related to CMDs(30). Low level of lymphocyte was associated with worse prognosis in patients with cardiovascular disease(31). Potential mechanisms include increased lymphocytes apoptosis and down-regulated lymphocyte proliferation and differentiation(32). Monocytes are important circulating leukocytes in both innate and adaptive immunity. Proinflammatory monocytes would be recruited and infiltrated to target tissue in an inflammatory state, whereupon they may differentiate into macrophages and promoting the inflammation(33, 34). During the development of metabolic syndrome, the recruitment of M1 macrophages dramatically increased due to the adipose tissue inflammation. This process can boost the number of macrophages and lead to higher secretion levels of pro-inflammatory cytokines, like IL-β and TNF-α, which in turn promote the progression of cardiometabolic diseases(35). Moreover, atherosclerosis might have a role in this relationship as well. We noticed that NLR was highly associated with atherosclerosis, while monocyte is the major immune cell in the formation of atherosclerotic plaque(36–38). Accumulation of immune cells like monocyte and neutrophil contributes to the rupture of atherosclerosis plaque(28), which is known as the main risk factor for cardiovascular disease, stroke, and metabolic disorders(39). In this case, a higher SIRI level may be associated with increased CMD incidence owing to its tight link with atherosclerosis. Furthermore, it is suggested that the enhanced diagnostic value of SIRI may be attributed to the incorporation of monocyte levels, as opposed to NLR and SII.
There are some clinical implications for our study. First, SIRI is expected to be a promising non-invasive biomarker for identification of people with high risk of CMD and CMM. The combination of the SIRI and other cardiometabolic risk profiles in cardiometabolic risk screening may be helpful for early identification, diagnosis and treatment of CMM. Clinicians can adjust treatment strategies based on changes in SIRI, potentially preventing complications associated with CMM. Second, since inflammation appears to be responsible for long-term complications and poor prognosis in CMD patients, anti-inflammatory treatment like anti-IL-1β have been introduced in the clinical management(5). Given the higher ORs of SIRI for CMDs, further researches can explore interventions that modulate inflammation to mitigate CMM risk. Lifestyle modification such as having an anti-inflammatory diet was also help to reduce the incidence of CMD, based on the evidence from NHANES 2005–2012 with 17689 participants(40). Considering the easy accessibility and high diagnostic value of SIRI, monitoring SIRI level enables a comprehensive assessment of patient’s overall chronic inflammatory status and aids in determining the effect of long-term treatment. Besides, our findings also provide epidemiological evidence supporting the hypothesis that inflammation is a plausible contributor to the development of CMM.
Our major strength was the large sample size and representative sample selection due to the design of the NHANES database. Also, we evaluated the association of SIRI with different CMM status, which extend the clinical application of SIRI. Nevertheless, there are still some limitations should be mentioned. First, we cannot infer any causal relationship attributed to the cross-sectional study design. Further large-scale prospective research should be conducted in the future. Second, the complete blood counts used for SIRI calculation were only collected once, which may not precisely indicate the long-term inflammatory status. Longitudinal studies with dynamic change in SIRI are highly recommended in the future. Third, residual confounding factors are inevitable, although we have adjusted for some potential covariates.